Design, synthesis and computational approach of vanillyl-imidazolidinyl-sulfamethoxazole derivatives as potent antimicrobial candidates tackling microbial resistance.

Superbugs are dominating the world due to the misuse and overuse of antibiotics. This study designed and synthesised two sets of compounds, oxazolones (3a-3j) and their respective imidazolones (4a-4j) bearing a sulfonamide functional group, with increased efficacy and capability to tackle microbial resistance. The structural conformation of compounds was determined using different techniques, including (1)H/(13)C NMR, FT-IR, HRMS and elemental analysis. The binding affinity of the specific targets of these congeners were predicted through molecular docking. The docking results indicated that compounds 4j (-10.36 kcal mol(-1)) and 4g (-8.62 kcal mol(-1)) showed minimum binding energy with strong affinity against target penicillin-binding protein 2a of methicillin resistant S. aureus (MRSA) and C14α-demethylase (CYP51) of C. albicans, respectively. Furthermore, these compounds were investigated for their antimicrobial efficacies. Compared with gentamicin, the imidazolone-derived compounds 4d and 4g showed significant inhibition in-terms of zone of inhibition and MIC values. However, the oxazolone-derived compound 3i showed a maximum zone of inhibition of 20 mm against a MDR T. rubrum strain, which is better than that of ketoconazole. Following these findings, HOMO-LUMO analysis was carried out, and compound 4g showed the smallest energy gap of 3.15 eV. The antibacterial activity of imidazolones is more effective than oxazolones, whereas the action is reversed for fungal strains. To combat against resistant pathogens, multifaced treatments should be followed, and compounds such as 4d and 4g might play a significant role in this regard. The synthetic and biological outcome of the newer vanillyl-imidazolidinyl-sulfamethoxazole derivatives mark a footstep in the drug discovery pipeline in the bacterial resistance era.